title: Proximal tubule PPARα attenuates renal fibrosis and inflammation caused by unilateral ureteral obstruction.
abstract: We examined the effects of increased expression of proximal tubule peroxisome proliferator-activated receptor (PPAR)α in a mouse model of renal fibrosis. After 5 days of unilateral ureteral obstruction (UUO), PPARα expression was significantly reduced in kidney tissue of wild-type mice but this downregulation was attenuated in proximal tubules of PPARα transgenic (Tg) mice. When compared with wild-type mice subjected to UUO, PPARα Tg mice had reduced mRNA and protein expression of proximal tubule transforming growth factor (TGF)-β1, with reduced production of extracellular matrix proteins including collagen 1, fibronectin, α-smooth muscle actin, and reduced tubulointerstitial fibrosis. UUO-mediated increased expression of microRNA 21 in kidney tissue was also reduced in PPARα Tg mice. Overexpression of PPARα in cultured proximal tubular cells by adenoviral transduction reduced aristolochic acid-mediated increased production of TGF-β, demonstrating PPARα signaling reduces epithelial TGF-β production. Flow cytometry studies of dissociated whole kidneys demonstrated reduced macrophage infiltration to kidney tissue in PPARα Tg mice after UUO. Increased expression of proinflammatory cytokines including IL-1β, IL-6, and TNF-α in wild-type mice was also significantly reduced in kidney tissue of PPARα Tg mice. In contrast, the expression of anti-inflammatory cytokines IL-10 and arginase-1 was significantly increased in kidney tissue of PPARα Tg mice when compared with wild-type mice subjected to UUO. Our studies demonstrate several mechanisms by which preserved expression of proximal tubule PPARα reduces tubulointerstitial fibrosis and inflammation associated with obstructive uropathy.
authors.affiliation: Division of Nephrology, Univ. of Arkansas for Medical Sciences, 4301 West Markham St., Slot 501, Little Rock, AR 72205, USA.
authors.forename: Shenyang
authors.initials: S
authors.lastname: Li
authors.forename: Nithya
authors.initials: N
authors.lastname: Mariappan
authors.forename: Judit
authors.initials: J
authors.lastname: Megyesi
authors.forename: Brian
authors.initials: B
authors.lastname: Shank
authors.forename: Krishnaswamy
authors.initials: K
authors.lastname: Kannan
authors.forename: Sue
authors.initials: S
authors.lastname: Theus
authors.forename: Peter M
authors.initials: PM
authors.lastname: Price
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
authors.forename: Didier
authors.initials: D
authors.lastname: Portilla
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D034341:Aristolochic Acids / Q000494:pharmacology; D051940:B7-2 Antigen / Q000096:biosynthesis; D024042:Collagen Type I / Q000096:biosynthesis; D024141:Collagen Type IV; D015536:Down-Regulation; D005355:Fibrosis; D016753:Interleukin-10 / Q000096:biosynthesis; D007674:Kidney Diseases / Q000209:etiology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D007797:Laminin / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis; D009393:Nephritis / Q000517:prevention & control; D047493:PPAR alpha / Q000096:biosynthesis / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014517:Ureteral Obstruction / Q000150:complications*
chemical_list: D034341:Aristolochic Acids; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D024042:Collagen Type I; D024141:Collagen Type IV; C556062:IL10 protein, mouse; D007797:Laminin; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D047493:PPAR alpha; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; C000228:aristolochic acid I; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: interleukin-10; peroxisome proliferator-activated receptor; transforming growth factor-β